Human SOCS3 blocking peptide

Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10mgkg(<-1) per day, intraperitoneally, for 2 weeks) increased the release of endothelial NO to relieve the vasodilatory response and improved the endothelial leptin resistance in the aorta of HFD-fed rats. These results suggest that ASM downregulation reverses endothelial leptin resistance, and consequently improves vascular endothelial dysfunction. This study highlighted ASM as a potential therapeutic target for endothelial leptin resistance.

Resident alveolar macrophages (AMs) suppress allergic inflammation in murine asthma models. Previously we reported that resident AMs can blunt inflammatory signaling in alveolar epithelial cells (ECs) by transcellular delivery of suppressor of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs). Here we examined the role of vesicular SOCS3 secretion as a mechanism by which AMs restrain allergic inflammatory responses in airway ECs. Bronchoalveolar lavage fluid (BALF) levels of SOCS3 were reduced in asthmatics and in allergen-challenged mice. Ex vivo SOCS3 secretion was reduced in AMs from challenged mice and this defect was mimicked by exposing normal AMs to cytokines associated with allergic inflammation. Both AM-derived EVs and synthetic SOCS3 liposomes inhibited the activation of STAT3 and STAT6 as well as cytokine gene expression in ECs challenged with IL-4/IL-13 and house dust mite (HDM) extract. This suppressive effect of EVs was lost when they were obtained from AMs exposed to allergic inflammation-associated cytokines. Finally, inflammatory cell recruitment and cytokine generation in the lungs of OVA-challenged mice were attenuated by intrapulmonary pretreatment with SOCS3 liposomes. Overall, AM secretion of SOCS3 within EVs serves as a brake on airway EC responses during allergic inflammation, but is impaired in asthma. Synthetic liposomes encapsulating SOCS3 can rescue this defect and may serve as a framework for novel therapeutic approaches targeting airway inflammation.